Albert J. Chang

RADIOTHERAPY FOR EPIDERMOID CARCINOMA OF THE ANUS: THIRTY YEARS' EXPERIENCE

PURPOSEnTo evaluate the factors associated with disease control and morbidity after radiotherapy for anal carcinoma.nnnMETHODS AND MATERIALSnBetween 1975 and 2005, 194 patients with localized epidermoid anal carcinoma underwent radiotherapy. Treatment evolved from radiotherapy with or without surgery, to preoperative chemoradiotherapy, to definitive chemoradiotherapy (CRT). The radiotherapy techniques also evolved.nnnRESULTSnWith a median follow-up of 61 months, 57 patients had persistence or recurrence, 9 of whom were successfully salvaged, resulting in 146 (75%) ultimately free of disease (UNED). Univariate analysis for UNED survival showed a strong association with the T and N stage (5-year UNED rate, 88.5% +/- 3.4% for those with Stage T1-T2N0; 70.1% +/- 4.2% for Stage T3N0; and 52.7% +/- 6.6% for Stage III; p > .001) and mobility on palpation (5-year UNED rate, 89.2% +/- 4.6% for those with mobile tumors vs. 59.3% +/- 6.1% for those with tethered/fixed tumor; p > .001). No association was found with gender, age, preoperative vs. definitive CRT, or human immunodeficiency virus status. The 20 human immunodeficiency virus+ patients all received CRT. The radiotherapy factors associated with Grade 3 or greater late morbidity included anorectal morbidity with tumor dose (29% with a dose > or =55 Gy vs. 9% otherwise), small bowel injury with technique (9% with anteroposterior-posteroanterior supine vs. 0.7% with multiple fields prone), and bone injury with femoral head dose (9% with a dose of > or =44 Gy vs. 0.7% otherwise). Of the 194 patients, 56 had 68 additional malignancies, mainly either antedating the anal cancer or outside the radiation fields.nnnCONCLUSIONnOur results have confirmed that CRT is an effective approach. Patients with human immunodeficiency virus can be treated with CRT. Tumor mobility significantly predicts the outcome; the implications for management are discussed. We also discuss the treatment planning implications of the late morbidity findings. The substantial incidence of additional malignancies underscores the importance of full oncologic screening during follow-up.

89Zr-Radiolabeled Trastuzumab Imaging in Orthotopic and Metastatic Breast Tumors.

The human epidermal growth factor receptor 2 (HER2/neu) is overexpressed in 20–30% of breast cancers and is associated with tumor growth, angiogenesis, and development of distant metastases. Trastuzumab, an anti-HER2 monoclonal antibody, is used for the treatment of HER2 positive breast cancer and clinical efficacy of this agent is dependent on HER2 expression. Targeted PET imaging of HER2 with radiolabeled trastuzumab may be used to determine HER2 expression levels and guide therapy selection. The purpose of the current study was to evaluate a facile 89Zr-trastuzumab preparation method that can be efficiently applied for clinical grade production. Also, relative HER2 expression levels in orthotopic and metastatic breast cancer models were assessed by PET imaging using the 89Zr-trastuzumab produced by this simpler method.

Development and characterization of 89Zr-labeled panitumumab for immuno-positron emission tomographic imaging of the epidermal growth factor receptor.

The epidermal growth factor receptor (EGFR) is overexpressed in the majority of malignancies and has been associated with poor outcomes. Panitumumab, an anti-EGFR monoclonal antibody that binds to the extracellular binding domain of EGFR, is increasingly used with radiotherapy and chemotherapy but has associated toxicities. The purpose of this study was to develop and characterize a novel targeted imaging agent for the EGFR using radiolabeled panitumumab. Flow cytometry studies were performed to evaluate EGFR expression in several cell lines. Desferrioxamine-Bz-NCS (DFO) was conjugated to panitumumab and labeled with (89)Zr. Cell uptake studies were performed in four cell lines. For biodistribution studies and micro-positron emission tomography/computed tomography (PET/CT), mouse xenograft models were generated using the same cell lines. PET was performed, and tumors and select organs were harvested for biodistribution studies. Panitumumab was radiolabeled with (89)Zr with high radiochemical purity and specific activity and was found to be stable in serum. Cell binding studies demonstrated that radiotracer uptake in cells correlated with the degree of EGFR expression. MicroPET/CT imaging studies demonstrated a high intensity of (89)Zr-panitumumab in A431 and HCT 116 tumors in comparison with the EGFR-negative tumors. Biodistribution studies confirmed the results from the imaging studies. (89)Zr-panitumumab imaging of EGFR-positive tumors demonstrated levels of radiotracer uptake associated with EGFR expression.

Detection of Rapalog-Mediated Therapeutic Response in Renal Cancer Xenografts Using 64Cu-bevacizumab ImmunoPET

The importance of neovascularization for primary and metastatic tumor growth fostered numerous clinical trials of angiogenesis inhibitors either alone or in combination with conventional antineoplastic therapies. One challenge with the use of molecularly targeted agents has been the disconnection between size reduction and tumor biologic behavior, either when the drug is efficacious or when tumor resistance emerges. Here, we report the synthesis and characterization of 64Cu-NOTA-bevacizumab as a PET imaging agent for imaging intratumoral VEGF content in vivo. 64Cu-NOTA-bevacizumab avidly accumulated in 786-O renal carcinoma xenografts with lower levels in host organs. RAD001 (everolimus) markedly attenuated 64Cu-NOTA-bevacizumab accumulation within 786-O renal carcinoma xenografts. Tumor tissue and cellular molecular analysis validated PET imaging, demonstrating decreases in total and secreted VEGF content and VEGFR2 activation. Notably, 64Cu-NOTA-bevacizumab PET imaging was concordant with the growth arrest of RAD001 tumors. These data suggest that immunoPET targeting of angiogenic factors such as VEGF could be a new class of surrogate markers complementing the RECIST criteria in patients receiving molecularly targeted therapies.

Prognostic value of 18F-FDG PET metabolic parameters in oropharyngeal squamous cell carcinoma

ObjectiveTo evaluate whether pretreatment metabolic parameters obtained from positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) can improve risk prediction for patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive intensity-modulated radiation therapy (IMRT).MethodsBetween 2003 and 2009, 86 patients with OPSCC had FDG-PET/CT prior to treatment with definitive IMRT. Chemotherapy was administered to 90xa0% of the patients. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax), mean SUV (SUVmean), and inverse coefficient of variation (1/CoV) were analyzed for the primary tumor alone and the total of the primary tumor and involved lymph nodes.ResultsMedian follow-up time for surviving patients was 41xa0months. On univariate analysis, total MTV and total TLG were significant predictors of disease-free survival (DFS) and overall survival (OS). SUVmax, SUVmean, and 1/CoV failed to predict DFS or OS. On multivariate analysis controlling for T- and N-classification, total MTV remained a significant predictor of DFS and OS. The optimal cutpoint for total MTV was 20.5xa0ml. A total MTV >20.5xa0ml was associated with a 4.13-fold increased risk of death (95xa0% confidence interval [CI], 2.12–8.05; pu2009<u20090.0001). Total MTV remained a significant predictor of DFS and OS for the subgroups with p16-positive (nu2009=u200925) and p16-negative (n =18) cancer.ConclusionTotal MTV is an independent predictor of DFS and OS for patients with OPSCC treated with definitive radiotherapy. Total MTV remained predictive of DFS and OS for both p16-positive and p16-negative cancer.

Roles of Atox1 and p53 in the trafficking of copper-64 to tumor cell nuclei: implications for cancer therapy.

Owing to its cytotoxicity, free copper is chelated by protein side chains and does not exist in vivo. Several chaperones transport copper to various cell compartments, but none have been identified that traffic copper to the nucleus. Copper-64 decays by β+ and β− emission, allowing positron emission tomography and targeted radionuclide therapy for cancer. Because the delivery of 64Cu to the cell nucleus may enhance the therapeutic effect of copper radiopharmaceuticals, elucidation of the pathway(s) involved in transporting copper to the tumor cell nucleus is important for optimizing treatment. We identified Atox1 as one of the proteins that binds copper in the nucleus. Mouse embryonic fibroblast cells, positive and negative for Atox1, were used to determine the role of Atox1 in 64Cu transport to the nucleus. Mouse embryonic fibroblast Atox1+/+ cells accumulated more 64Cu in the nucleus than did Atox1−/− cells. HCTxa0116 colorectal cancer cells expressing p53 (+/+) and not expressing p53 (−/−) were used to evaluate the role of this tumor suppressor protein in 64Cu transport. In cells treated with cisplatin, the uptake of 64Cu in the nucleus of HCTxa0116 p53+/+ cells was greater than that in HCTxa0116 p53−/− cells. Atox1 expression increased in HCTxa0116 p53+/+ and p53−/− cells treated with cisplatin; however, Atox1 localized to the nuclei of p53+/+ cells more than in the p53−/− cells. The data presented here indicate that Atox1 is involved in copper transport to the nucleus, and cisplatin affects nuclear transport of 64Cu in HCTxa0116 cells by upregulating the expression and the nuclear localization of Atox1.

Video surface image guidance for external beam partial breast irradiation

OBJECTIVEnAccelerated partial breast irradiation is an emerging treatment option for early stage breast cancer. With accelerated partial breast irradiation, patient setup, and target registration accuracy is vital. The current study compared various methods for isocenter placement accuracy.nnnMETHODS AND MATERIALSnTwenty-three patients treated on an institutional-approved partial breast irradiation protocol were monitored at each treatment fraction. All patients included in this study underwent clip placement at the time of surgery. Patients underwent computed tomographic simulation and surface contours were used to reconstruct a reference surface map. At the treatment machine, patients were initially positioned by laser alignment to tattoos. Orthogonal kilovoltage imaging of the chest wall, followed by video surface mapping of the breast, was performed. This video surface map was matched to the reference surface map to adjust the couch position. Verification orthogonal chest wall imaging and video surface mapping was again performed. The accuracy of setup by laser, orthogonal imaging of the chest wall, and surface alignment was retrospectively compared using the centroid clip position as the reference standard. The impact of setup error by surface alignment and by orthogonal kilovoltage imaging on planning target volume coverage was then calculated.nnnRESULTSnLaser-based positioning resulted in a residual setup error of 3.9 ± 3.7 mm, 4.6 ± 3.9 mm, and 4.3 ± 4.5 mm in the posterior-anterior (P-A), inferior-superior (I-S), and left-right (L-R) directions, respectively, using clips as the reference standard. Setup based on bony anatomy with orthogonal imaging resulted in residual setup error of 3.2 ± 2.9 (P-A), 4.2 ± 3.5 (I-S), and 4.7 ± 5.3 mm (L-R). Setup with video surface mapping resulted in a residual setup error of 1.9 ± 2.2, 1.8 ± 1.9, and 1.8 ± 2.1 mm in the P-A, I-S, and L-R directions, respectively. Vector spatial deviation was 8.8 ± 4.2, 8.3 ± 3.8, and 4.0 ± 2.3 mm with laser, chest wall on board imaging, and video surface mapping based setup, respectively. Setup by video surface mapping resulted in improved dosimetric coverage of the planning target volume when compared with orthogonal imaging of the chest wall (V100 96.0% ± 0.1% vs 89.3% ± 0.2%; V95 99.7% ± 0.01% vs 98.6% ± 0.01%, P < .05).nnnCONCLUSIONSnVideo surface mapping of the breast is a more accurate method for isocenter placement in comparison to conventional laser-based alignment or orthogonal kilovoltage imaging of the chest wall.

Clinical Perspectives on Dose Escalation for Non-Small-Cell Lung Cancer

Lung cancer remains the leading cause of cancer death in the United States. The standard of care for patients with locally advanced non-small-cell lung cancer is radiation plus chemotherapy. The nationally accepted standard radiation prescription dose has remained at 60-63 Gy for more than 30 years, with local failure rates reaching 85% and median survival rates of approximately 17 months. With smaller treatment volumes and the increased conformality of radiation delivery, the administration of higher radiation doses to the target while minimizing dose to critical structures is feasible. Clinical outcome is improved while minimizing toxicity. Recent prospective trials escalating doses to 74 Gy with concurrent chemotherapy have demonstrated promise with improved survival rates and acceptable toxicity rates.

Split-Field Helical Tomotherapy With or Without Chemotherapy for Definitive Treatment of Cervical Cancer

OBJECTIVEnThe objective of this study was to investigate the chronic toxicity, response to therapy, and survival outcomes of patients with cervical cancer treated with definitive pelvic irradiation delivered by helical tomotherapy (HT), with or without concurrent chemotherapy.nnnMETHODS AND MATERIALSnThere were 15 patients with a new diagnosis of cervical cancer evaluated in this study from April 2006 to February 2007. The clinical stages of their disease were Stage Ib1 in 3 patients, Ib2 in 3, IIa in 2, IIb in 4, IIIb in 2, and IVa in 1 patient. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) simulation was performed in all patients. All patients received pelvic irradiation delivered by HT and high-dose-rate (HDR) brachytherapy. Four patients also received para-aortic irradiation delivered by HT. Thirteen patients received concurrent chemotherapy. Patients were monitored for chronic toxicity using the Common Terminology Criteria for Adverse Events version 3.0 criteria.nnnRESULTSnThe median age of the cohort was 51 years (range, 29-87 years), and the median follow-up for all patients alive at time of last follow-up was 35 months. The median overall radiation treatment time was 54 days. One patient developed a chronic Grade 3 GI complication. No other Grade 3 or 4 complications were observed. At last follow-up, 3 patients had developed a recurrence, with 1 patient dying of disease progression. The 3-year progression-free and cause-specific survival estimates for all patients were 80% and 93%, respectively.nnnCONCLUSIONnIntensity-modulated radiation therapy delivered with HT and HDR brachytherapy with or without chemotherapy for definitive treatment of cervical cancer is feasible, with acceptable levels of chronic toxicity.

Intratumoral Heterogeneity of 64Cu-ATSM Uptake is a Prognostic Indicatorin Patients with Cervical Cancer

Introduction: Intratumoral heterogeneity determined by FDG-PET is a poor prognostic factor in cervical cancer. Cu- nATSM has been used to evaluate hypoxia in cervical cancer. In this study, FDG and 64Cu-ATSM uptake patterns were ncompared and the prognostic significance of 64Cu-ATSM heterogeneity was determined. nMethods: 15 patients with cervical cancer who underwent pretreatment 64Cu-ATSM- and FDG-PET/CT were nincluded. The 64Cu-ATSM- and FDG-PET/CT images were co-registered and tumor volumes were autocontoured for neach image set in 10% increments of the SUVmax ranging from 40% to 80%. The hypoxic fraction defined by 64Cu-ATSM nuptake was determined. Concordance between 64Cu-ATSM and FDG uptake was determined by Dice’s coefficient. nHeterogeneity of 64Cu-ATSM and FDG uptake was calculated as the variance of the 40-80% isothreshold volumes. The nassociation between heterogeneity of 64Cu-ATSM uptake with tumor-specific factors and outcomes was determined. nResults: The hypoxic fraction ranged from 0.773 ± 0.013 to 0.087 ± 0.010 as defined by the 40% to 80% Cu-ATSM nisothreshold volumes, respectively. Dice’s similarity coefficients for the FDG and 64Cu-ATSM 40 to 80% isothreshold nvolumes ranged from 0.476 ± 0.012 to 0.112 ± 0.017. Greater 64Cu-ATSM heterogeneity was associated with increased nrisk of lymph node metastasis at diagnosis (p<0.01), persistent disease after therapy, (p<0.01), and decreased median nprogression-free survival (11 months vs. not reached, p=0.03). nConclusion: Significant fractions of cervical tumors are hypoxic. Regions of highest 64Cu-ATSM and FDG uptake nwere discordant. Elevated 64Cu-ATSM heterogeneity may predict for increased risk of lymph node metastases, decreased nresponsiveness to treatment, and decreased progression-free survival.